The goal of this interdisciplinary study is to quantitatively define the pattern of physiological, morphological, and transmitter distribution changes which occurs in epileptogenic neocortical human brain tissue. To do this, we will examine normal and epileptogenic brain tissue removed during surgery for epilepsy, using in vitro slice electrophysiology, standard histology, and immunocytochemistry. A crucial feature will be the quantitative definition of the epileptogenic vs. normal nature of the tissue using chronic subdural recordings with implanted plate electrodes. With this knowledge, we expect a better understanding of the pathological mechanisms which result in epiletic neural activity, and a resulting improvement in our ability to treat epilepsy. The major working hypothesis which unifies the experiments in this proposal is that chronic temporal epilepsy is caused by a relatively selective loss of inhibitory synaptic mechanisms. This loss produces a constellation of effects which combine to produce excessively synchronized neural activity. The major advantage of our proposal will be the interdiscipinary quantitative analysis many different changes (electrophysiological, morphological and transmitter distribution) in the same piece of tissue, and to statically correlate these changes with a quantified index of the epileptogenicity of the tissue provided by the extensive chronic subdural recordings. This will allow us to compare epileptogenic tissues with more normal tissue from the same location in different patients and from different locations in the same patient.